Drug delivery systems have been increasingly applied to treatment of various diseases as ideal drug application forms. Of these, developments for improving an circulation in blood by modifying drugs with polyethylene glycol have been widely performed and drugs obtained by modifying cytokines such as interferon and GCSF with polyethylene glycol have been placed on the market and have been widely used.
In general, as elimination paths of a drug applied into the body, there may be mentioned filtration excretion from kidney glomeruli and treatment by a reticuloendothelial system (RES system) represented by Kupper cell. Since the glomeruli function as a size-dependent filtration membrane, the filtration excretion path can be avoided by modifying the drug with a polyoxyalkylene to enlarge the size. Also, in the RES system, the drug is phagocytized by RES recognition through non-specific interaction (opsonization) but the polyoxyalkylene-modified compound exhibits a low interaction with a living body component, so that the RES recognition can be avoided. For such reasons, polyoxyalkylene derivatives have been widely used as DDS materials for elongating the retaining property in blood.
Hitherto, in the polyoxyalkylene derivatives, a type of the derivatives having one reactive functional group at a terminal end of methoxypolyethylene glycol is common but recently, there has been developed a polyoxyalkylene derivative having two proximate reactive functional groups. Since such derivative has two functional groups in proximate positions, it has effects that a metal atom is chelated, it acts as a pseudoantibody through bonding of an antibody fragment to each functional group, and an amount of a low-molecular-weight drug bonded can be increased.
WO99/45964 discloses a compound represented by the following formula, wherein two reactive functional groups and one polyoxyalkylene chain are bonded via a tertiary carbon: POLY-Y—CHXX′ (X and X′ are a reactive functional group)
It is known that the retaining property in blood, which is a characteristic of the polyoxyalkylene-modified compound, is improved as the molecular weight increases. On the other hand, when the molecular weight reaches a level of several tens of thousands, there is a problem that viscosity of a polyoxyalkylene-modified drug solution increases and drug design becomes difficult.
Moreover, in the disclosed synthetic method, two functional groups are introduced into a terminal hydroxyl group of methoxypolyethylene glycol. In the case of this method, since the reaction is an introducing reaction into a polymer terminal end, there is a concern that a functional group-introducing ratio decreases and thus a purity of the polyoxyalkylene derivative decreases.
Furthermore, a hydrogen attached to a tertiary carbon has a high acidity and there is a problem that a tertiary cation is formed with a base and a side reaction tends to occur.
U.S. Pat. No. 6,153,655 discloses a structure wherein a branched chain and a drug are introduced into both terminal ends of polyethylene glycol via an amide bond.
U.S. Pat. No. 6,251,382 and U.S. Pat. No. 6,824,766 disclose compounds obtained by activating a methoxypolyethylene glycol terminal end, subsequently reacting the terminal end with an amino group-containing core skeleton compound such as 1,3-diaminopropanol to introduce a polyethylene glycol chain via a urethane bond, and then introducing a plurality of functional groups into remaining hydroxyl groups.
Similarly, International Laid-Open No. 2005/061005 also discloses compounds obtained by activating a methoxypolyethylene glycol terminal end, subsequently reacting the terminal end with a core skeleton compound to introduce a polyethylene glycol chain via a urethane bond, and then introducing a plurality of functional groups into remaining functional groups.
In the derivatives disclosed therein, a polyoxyalkylene chain and a core skeleton compound such as lysine are bonded via an amide bond, a carbamate bond, or an ester bond, so that there is a problem that these bonds are liable to undergo hydrolysis during storage or during a reaction under alkaline conditions and, as a result, the polyoxyalkylene chain is dissociated.
Moreover, in the production thereof, since the production is performed via a step of reacting a core skeleton compound such as lysine with a reactive polyoxyalkylene derivative, there is a problem that impurities different in the introduced number of polyoxyalkylene chains are formed. It is industrially difficult to purify such polymeric compounds one another.
Furthermore, in the disclosed compounds, an asymmetric carbon is present in the core skeleton and there is a problem that this is not homogeneous when bonding to a drug and development to a medicament are considered.
Based on such background, there has been required a polyfunctional polyoxyalkylene compound having a high stability, exhibiting easiness of obtaining homogeneity owing to absence of any asymmetric carbon in the molecule, and having a low viscosity even when molecular weight increases.